Anticholinesterase and Antioxidant Activity of New Binary Conjugates of γ-Carbolines.

The synthesized new binary conjugates of tetrahydro-γ-carbolines, which contained ditriazole spacers of different length, exhibited considerable anticholinesterase and antioxidant activity as well as the potential ability to block the acetylcholinesterase-induced aggregation of ß-amyloid in contrast to the original prototype Dimebon. This makes the compounds promising candidates for further investigation as drugs for the treatment of Alzheimer's disease. Special attention should be given to the conjugate containing the hexamethylene intertriazole spacer, which can be considered as a leader in this series of compounds.

N,N'-Substituted Selenoureas as Polyfunctional Antioxidants.

Analysis of antioxidant activity of synthesized selenourea derivatives showed that N,N'-substituted selenoureas inhibited Fe(III)-induced LPO in rat brain homogenate. On the other hand, oxygen- and sulfur-containing analogs exhibited no antioxidant activity or even slight prooxidant activity. Intramolecular alkylation of selenium atom also led to loss of antioxidant activity. Thus, antioxidant activity of the compounds was due to the presence of a nonalkylated selenium atom in N,N'-substituted selenourea analogs.

Antioxidative activity of ferrocenes bearing 2,6-di-tert-butylphenol moieties.

The antioxidative activity of ferrocenes bearing either 2,6-di-tert-butylphenol or phenyl groups has been compared using DPPH (1,1-diphenyl-2-picrylhydrazyl) test and in the study of the in vitro impact on lipid peroxidation in rat brain homogenate and on some characteristics of rat liver mitochondria. The results of DPPH test at 20 degrees C show that the activity depends strongly upon the presence of phenolic group but is improved by the influence of ferrocenyl fragment. The activity of N-(3,5-di-tert-butyl-4-hydroxyphenyl)iminomethylferrocene (1), for instance, was 88.4%, which was higher than the activity of a known antioxidant 2,6-di-tert-butyl-4-methylphenol (BHT) (48.5%), whereas the activity of N-phenyl-iminomethylferrocene 2 was almost negligible -2.9%. The data obtained demonstrate that the compounds with 2,6-di-tert-butylphenol moiety are significantly more active than the corresponding phenyl analogues in the in vitro study of lipid peroxidation in rat brain homogenate. Ferrocene 1 performs a promising behavior as an antioxidant and inhibits the calcium-dependent swelling of mitochondria. These results allow us to propose the potential cytoprotective (neuroprotective) effect of ditopic compounds containing antioxidant 2,6-di-tert-butylphenol group and redox active ferrocene fragment.

Molecular basis of discrepancies in neurotoxic properties among 1-methyl-4-aryl-1,2,3,6-tetrahydropyridines.

The relationship between structural specificity of the main stages of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) action and the display of parkinsonogenic properties among homologous structures in a number of 4-tolyl derivatives of MPTP has been studied. All the compounds are better substrates for monoamine oxidase (MAO) than MPTP. MAO is inactivated during the reaction according to a mechanism of irreversible inhibition by 2,3-dihydropyridinium metabolite. All the tolyl derivatives are stronger inhibitors of MAO than 1-methyl-2,3-dihydropyridinium (MPDP). A significant contribution of enzyme inhibition to the catalytic conversion of the substrate leads to the fact that substrates having equal (para isomer) or even higher (meta isomer) values of catalytic parameters are oxidized by MAO to a lesser extent than MPTP. It has been found that all 4-arylpyridiniums (final products of MATP bioconversion) competitively and reversibly inhibit [14C]dopamine (DA) uptake in mouse brain synaptosomes. Affinity toward DA transporter characterized by KI (microM) is 0.37 +/- 0.04, 0.7 +/- 0.1, 2.0 +/- 0.15, 2.0 +/- 0.35 for MPP, and its o-, m-, and p-tolyl derivatives, respectively. Joint calculation of specificity factors for the processes discussed define the following rank order for the bio-delivery of MATP's metabolic produces into DA nerve terminals: o-tolyl > MPTP >> m-tolyl > p-tolyl. The regularity revealed is in good agreement with the observed relative potency of these compounds to cause dopaminergic neurodegeneration.